Methods for modulating fmr1 expression

Abstract

Provided are methods for increasing the amount or activity of FMR1 RNA, and in certain instances of increasing the amount of FMRP protein, in an animal. Such methods are useful to prevent or ameliorate at least one symptom of a Fragile X-Spectrum disorder. Such Fragile X-Spectrum disorders include FXS, FXTAS, and FXPOI.

1 - 57 . (canceled) 
     
     
         58 . A method of (i) increasing the amount of FMR1 RNA or FMRP protein in cells or tissues or (ii) decreasing the amount of a RAN translation product in cells or tissues, the method comprising contacting the cells or tissues with an oligomeric compound comprising a modified oligonucleotide consisting of 10-30 linked nucleosides and having a nucleobase sequence complementary to at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases of an equal length portion of nucleobases 3001-3042 of SEQ ID NO: 1. 
     
     
         59 . The method of  claim 58 , wherein the modified oligonucleotide consists of 12-30, 16-30, 16-20, or 18-20 linked nucleosides. 
     
     
         60 . The method of  claim 58 , wherein the modified oligonucleotide comprises at least one modified nucleoside. 
     
     
         61 . The method of  claim 60 , wherein the at least one modified nucleoside comprises a modified sugar moiety. 
     
     
         62 . The method of  claim 61 , wherein the modified sugar moiety is a bicyclic sugar moiety or a non-bicyclic modified sugar moiety. 
     
     
         63 . The method of  claim 58 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         64 . The method of  claim 63 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         65 . The method of  claim 58 , wherein the modified oligonucleotide comprises at least one modified nucleobase. 
     
     
         66 . The method of  claim 58 , wherein the RAN translation product is any of polyglycine, polyalanine, and polyarginine. 
     
     
         67 . A method of treating an animal having a Fragile X-spectrum disorder, the method comprising administering to the animal an oligomeric compound comprising a modified oligonucleotide consisting of 10-30 linked nucleosides and having a nucleobase sequence complementary to at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases of an equal length portion of nucleobases 3001-3042 of SEQ ID NO: 1, wherein the administering preserves neurons. 
     
     
         68 . The method of  claim 67 , wherein the Fragile X-Spectrum disorder is FXS, FXTAS, or FXPOI. 
     
     
         69 . The method of  claim 67 , wherein the oligomeric compound is administered prior to detection of at least one symptom of a Fragile X-Spectrum disorder. 
     
     
         70 . The method of  claim 67 , wherein the amount of total FMR1 RNA is increased in the animal. 
     
     
         71 . The method of  claim 67 , wherein the amount of total FMRP protein is increased in the animal. 
     
     
         72 . The method of  claim 67 , wherein the amount of a RAN translation product is reduced in the animal. 
     
     
         73 . The method of  claim 72 , wherein the RAN translation product is any of polyglycine, polyalanine, and polyarginine. 
     
     
         74 . The method of  claim 67 , wherein the animal is a human. 
     
     
         75 . A method of preserving neurons in an animal in need thereof, the method comprising administering to the animal a modified oligonucleotide consisting of 10-30 linked nucleosides and having a nucleobase sequence complementary to at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 contiguous nucleobases of an equal length portion of nucleobases 3001-3042 of SEQ ID NO: 1. 
     
     
         76 . The method of  claim 75 , wherein the animal has Fragile X-Spectrum disorder. 
     
     
         77 . The method of  claim 75 , wherein the animal is a human.